Maternal low-protein diet in rat pregnancy programs blood pressure through sex-specific mechanisms

Abstract
Animal models support human epidemiological studies in demonstrating a relationship between impaired fetal growth and risk of adult hypertension. Undernutrition during pregnancy exerts programming effects on the developing kidney, and modulation of angiotensin receptor (ATR) expression has been observed persisting into adult life. Fetal overexposure to glucocorticoids is thought to be central to the nutritional programming of blood pressure and may act through an interaction with ATR expression. Pregnant female Wistar rats were fed a control ( n = 6) or a maternal low-protein diet (MLP; n = 17) throughout pregnancy. The glucocorticoid dependency of MLP effects was tested using metyrapone, an inhibitor of corticosterone synthesis. MLP-fed rats were injected twice daily with metyrapone, metyrapone plus corticosterone, or vehicle over days 1–14 of pregnancy. At delivery, all animals were fed standard laboratory chow. MLP-exposed offspring 4 wk of age exhibited increased systolic blood pressure compared with controls ( P < 0.05), which proved to be glucocorticoid dependent in males only. AT1R mRNA expression was independent of in utero dietary treatment. AT2R mRNA expression was downregulated in MLP-exposed females only ( P < 0.05) and in a glucocorticoid-independent manner. Male offspring exhibited glucocorticoid-dependent hypertension with no modulation of renal ATR mRNA expression. In contrast, female offspring exhibited glucocorticoid-independent hypertension associated with reduced expression of renal AT2R mRNA. These data do not support the hypothesis that an interaction between glucocorticoid and ATR mRNA expression underlies the nutritional programming of blood pressure but instead suggest two independent mechanisms acting in a sex-specific manner.